Renal involvementin inborn errors of metabolism

[No conflict of interest]

Pierre Cochat, MD PhDProfessor of Pediatrics

Head, Center for Rare Renal Diseases NéphrogonesHospices Civils de Lyon & University Claude-Bernard, Lyon, France

Introduction

▪ Around 80 IEM with potential renal involvement…

▪ Classification into 13 groups…

Eimie - girl, 2.7 yrs

▪ Severe scoliosis in both parents

▪ Birth: 38 GA term, 3300 g, 50 cm, HC 34 cm

▪ Vitamine D: daily from birth to 1.5 yrs, then 1 load dose per year

▪ Immunization: ok

▪ Progressive deformation of both legs at the time of walking learning

▪ Plain x-ray at 2.5 yrs

Rickets

Eimie - girl, 2.7 yrs

▪ Clinical examination▪ Height 92.cm (+0,5 SD) – BW 13,2 kg (N)

▪ BP 88/60

▪ Intercondylar distance 6 cm

▪ Liver enlargement 4 cm

▪ Abdomen US

▪ Hepatomegaly▪ Heterogenous parenchyma▪ Small hypo- and hyperechogenic nodules▪ Normal gallbladder

▪ Mild renal enlargment▪ No abdominal mass▪ No lymph node

Eimie - girl, 2.7 yrs

▪ Biological investigations▪ Calcium 2.35 mmol/L

▪ Phosphate 0.57 mmol/L (N= 1.39-2.20)

▪ Bicarbonate 16 mmol/L

▪ Chloride 119 mmol/L

▪ Creatinine 17 mmol/L

▪ Alk. Phosph. 1251 IU/L (N<500)

▪ Platelet count 94 G/L

▪ ASAT 61 IU/L (N= 5-34)

▪ GGT 79 IU/L (N= 5-25)

▪ Diagnosis?

▪ Specific tests?

Eimie - girl, 2.7 yrs

▪ Diagnosis: Tyrosinemia type 1

▪ Specific tests After 2.5 mos on NTBC▪ Alpha-fetoprotein 2345 µg/L (N< 9) 415

▪ Urine succinyl-acetone 179 µmol/L (N< 1) < 1

▪ Comments▪ Incidence: 1/200,000 (Canada) to 1/2,000,000 live births (Europe)

▪ Autosomal recessive inheritance

▪ Most common presentation: acute liver failure in the 1st year of life

▪ Fumaryl-acetoacetase deficiency (enzyme for tyrosine degradation) - FAH, 15q23-q25

▪ Increased plasma delta aminolevulinic acid + urine succinyl-acetone▪ Liver toxicity: cirrhosis, hépatocarcinoma

▪ Kidney: Fanconi syndrome

▪ From 1990: NTBC (Orfandin®) – blocks tyrosine degradation – hyper-tyrosinemia▪ Risk of painful dermatological and ocular lesions

▪ Limitation of tyrosine intake (low protein diet + specific aminoacids supplements)

▪ Some patients may require liver Tx

1. IEM of aminoacids and peptides

▪ Cystinosis Fanconi - CKD

▪ Tyrosinemia type 1 Fanconi - CKD

▪ Lysinuric protein intolerance TIN - CKD

▪ Cystinuria Stones

▪ Propionic acidemia CKD

▪ Methylmalonic acidemia TIN - CKD

▪ Prolidase deficiency Lupus nephritis

▪ Alkaptonuria Black urine

▪ Homocystinuria Renal infaction

▪ Oxoprolinuria Stones

1. IEM of aminoacids and peptides

▪ Cystinosis Fanconi - CKD

▪ Tyrosinemia type 1 Fanconi - CKD

▪ Lysinuric protein intolerance TIN - CKD

▪ Cystinuria Stones

▪ Propionic acidemia CKD

▪ Methylmalonic acidemia TIN - CKD

▪ Prolidase deficiency Lupus nephritis

▪ Alkaptonuria Black urine

▪ Homocystinuria Renal infaction

▪ Oxoprolinuria Stones

Methylmalonic acidemia (MMA)

▪ Severe inborn error of catabolic pathway of branched-chain aminoacids, odd chain fatty acids and cholesterol leading to accumulation of MMA in the serum

▪ Caused by mutations▪ In the MUT gene encoding methylmalonylCoA mutase (isolated MMA)

▪ in the MMAA (CblA) and MMAB (CblB) genes encoding key enzymes of the metabolism of its cofactor, cobalamin (vitamin B12)

▪ These enzymes are expressed in many tissues, including liver and kidney

▪ Methylmalonyl CoA mutase can be completely deficient (mut°) or partially deficient with residual activity (mut−)

▪ Clinical presentation▪ Lethargy, vomiting, dehydration, metabolic acidosis and coma in the neonatal period

▪ Or later in case of partial deficiency

MMA - Management

▪ (Vitamin B12 in responsive patients)

▪ In nonresponsive patients: low-protein high-energy diet▪ Supplementary amino-acids avoiding the propiogenic ones (valine, isoleucine,

threonine and methionine)

▪ L-carnitine to prevent deficiency and increase the excretion of carnitine esters

▪ Antibiotics intermittently to reduce propionate production by gut flora

MMA – Renal involvement

▪ Proximal and/or distal tubular dysfunction

▪ Progressive tubulointerstitial disease

▪ Leading to ESRD in >50% of those with severe forms of MMA

▪ CKD can be present as early as 18 mo

▪ Decreased muscle mass renders creatinine assessement poorly predictive

MMA – Transplantation strategy

Molecular Genet Metab 2013

Transplantation 2016

2. IEM of fatty acids and ketone bodies

▪ CPT deficiency 1 RTA

▪ CPT deficiency 2 Renal cysts – CKD

▪ Fatty acid oxidation disorders Tubulopathy - AKI

3. IEM of carbohydrates

▪ Galactosemia Fanconi

▪ Glycogen storage disease type 1a Fanconi – Stones – FSGS

▪ Glycogen storage disease type 1b FSGS

▪ Fanconi-Bickel syndrome Fanconi – Hyperfiltration

▪ Hereditary fructose intolerance Fanconi – AKI

▪ Congenital lactase deficiency Nephrocalcinosis

▪ Glucose-galactose malabsorption Stones

▪ Transaldolase deficiency Tubulopathy – Stones

▪ Primary hyperoxalurias 1, 2, 3 Stones – CKD – Systemic inv.

▪ Renal glycosuria Glycosuria

▪ McArdle disease AKI - Myoglobinuria

3. IEM of carbohydrates

▪ Galactosemia Fanconi

▪ Glycogen storage disease type 1a Fanconi – Stones – FSGS

▪ Glycogen storage disease type 1b FSGS

▪ Fanconi-Bickel syndrome Fanconi – Hyperfiltration

▪ Hereditary fructose intolerance Fanconi – AKI

▪ Congenital lactase deficiency Nephrocalcinosis

▪ Glucose-galactose malabsorption Stones

▪ Transaldolase deficiency Tubulopathy – Stones

▪ Primary hyperoxalurias 1, 2, 3 Stones – CKD – Systemic inv.

▪ Renal glycosuria Glycosuria

▪ McArdle disease AKI - Myoglobinuria

Glycogen Storage Disease Type 1

▪ Autosomal recessive inheritance

▪ Defects in the G6Pase complex (conversion from G6P into glucose)

▪ Accumulation of glycogen in the liver, kidney and intestine mucosa

▪ Poor tolerance to fasting: hypoglycemia, lactic acidosis, hyperuricemia

▪ Growth retardation, hepatomegaly (risk of hepatocarcinoma)

▪ Improved prognosis due to better dietary/metabolic management (frequent feed + uncooked cornstarch)

▪ Renal dysfunction in the long term: PU, HTN, CKD

▪ Pathophysiology: diabetes mellitus + specific GSD-1 involvement

GSD-1: Renal involvement

Renal tubular dysfunction

▪ Proximal tubular dysfunction: early feature (PU, enzymuria)

▪ Fanconi syndrome is rare

▪ Distal tubular dysfunction

▪ Higher risk of nephrolithiasis (hypercalciuria + hypocitraturia)

Glomerular dysfunction

▪ Hyperfiltration + albuminuria in most patients > 25 yrs of age

▪ Progressive FSGS with decline in GFR

▪ Treatment with ACEi/ARB slows down the progression of CKD

▪ Some patients may require combined liver-kidney Tx

4. IEM of energy (mitochondrial cytopathies)

▪ GRACILE syndrome Fanconi

▪ Pyruvate carboxylase deficiency RTA

▪ Kearns Sayre syndrome Bartter like

▪ MELAS FSGS

▪ MIDD FSGS

▪ NN encephalopathy-cardiomyopathy CAKUT

▪ Coenzyme Q10 deficiencies SRNS – Tubulopathy

▪ Mitochondrial ribonucleotide sub. 2 Tubulopathy

▪ Pearson syndrome Fanconi

▪ Complex III deficiency Tubulopathy

▪ Complex IV deficiency CKD

▪ mtDNA depletion tubulopathy

5. IEM of purines, pyramidines and nucleotides

▪ SCID-ADA deficiency RTA, proteinuria

▪ Lesch-Nyhan syndrome Stones, AKI, CKD

▪ Familial hyperuricemic nephropathy Gout, stones, CKD

▪ APRT deficiency Stones 2,8-dihydroxyadenine

▪ Hereditary renal hypouricemia Stones, AKI

▪ Hereditary orotic aciduria Stones

▪ Xanthinuria type 1 Stones

▪ Xanthinuria type 2 AKI

▪ PRPP synthetase superactivity Stones

5. IEM of purines, pyramidines and nucleotides

▪ SCID-ADA deficiency RTA, proteinuria

▪ Lesch-Nyhan syndrome Stones, AKI, CKD

▪ Familial hyperuricemic nephropathy Gout, stones, CKD

▪ APRT deficiency Stones 2,8-dihydroxyadenine

▪ Hereditary renal hypouricemia Stones, AKI

▪ Hereditary orotic aciduria Stones

▪ Xanthinuria type 1 Stones

▪ Xanthinuria type 2 AKI

▪ PRPP synthetase superactivity Stones

Lesch-Nyhan syndrome

▪ Deficiency of hypoxanthine-guanine phosphribosyltransferase (HPRT)

▪ Lesh-Nyhan syndrome is the most severe form

▪ Prevalence: 1/380,000 (Canada) – 1/235,000 (Spain)

▪ X-linked recessive – Xq26 - > 300 diseases associated-mutations in HPRT1

▪ Uric acid overproduction – Nephrolithiasis and gout

▪ Progressive neurological involvement related to enzyme deficiency

▪ Neurological manifestations▪ Severe action dystonia

▪ Choreoathetosis and ballismus

▪ Cognitive and attention deficit

▪ Self-injurious behaviour, sensitive to any kind of stimuli (pain, anxiousness, etc.)

Lesch-Nyhan syndrome

▪ Diagnosis: HPRT activity in erythrocytes + genotyping (prenatal diagnosis)

▪ Management▪ Allopurinol, adapted to avoid xanthine stones

▪ Spasticity: benzodiazepins, baclofen

▪ Physical rehabilitation: limited efficacy

▪ Stereotaxic neurosurgery: limited efficacy

▪ Psychological care of the child and parents

▪ Self-injurious behaviour: physical restraints, behavioural and physical actions

Lesh-Nyhan syndrome: Self-injurious behavior

With permission

Torres Orphanet J Rare Dis 2007

6. IEM of Sterols

▪ Smith-Lemli-Opitz syndrome Renal cysts, CAKUT

▪ Conradi Hunnerman syndrome Renal hypo/dysplasia

▪ CHILD syndrome Renal hypo/dysplasia

▪ Desmosterolosis Renal hypo/dysplasia

▪ Antley-Bixler syndrome Renal hypo/dysplasia

7. IEM of lipid and lipoprotein metabolism

▪ Lecithin: cholesterol acetyltransferase deficiency PU, GN, CKD

▪ Lipoprotein glomerulopathy PU, GN, CKD

8. IEM of Glycosylation

▪ Type 1a Proteinuria – NS – cysts

▪ Type 1h Renal cysts – Tubulopathy

▪ Type 1l Renal cysts

▪ B3GALTL (Peter-plus syndrome) CAKUT

▪ Type 2f Proteinuria

▪ Type 2e CAKUT - Tubulopathy

9. Lysosomal disorders

▪ Fabry’s disease RTA – proteinuria – CKD

▪ Metachromatic leucodystrophy RTA – Tubulopathy

▪ Galactosialidose Proteinuria – CKD

▪ MPS type 1 (Hurler) NS – Hypertension

▪ Infantile sialic acid storage disease Proteinuria – NS

▪ Gaucher’s disease Proteinuria – Acute GN

▪ Action myoclonus renal failure Sd Proteinuria - FSGS

9. Lysosomal disorders

▪ Fabry’s disease RTA – proteinuria – CKD

▪ Metachromatic leucodystrophy RTA – Tubulopathy

▪ Galactosialidose Proteinuria – CKD

▪ MPS type 1 (Hurler) NS – Hypertension

▪ Infantile sialic acid storage disease Proteinuria – NS

▪ Gaucher’s disease Proteinuria – Acute GN

▪ Action myoclonus renal failure Sd Proteinuria - FSGS

Fabry’s disease

▪ X-linked inherited lysosomal storage disorder

▪ Deficiency of α-galactosidase A

▪ Progressive accumulation of globotriaosylceramide (Gb3)

▪ Signs and symptoms can begin in early childhood and lead to life-threatening renal, cardiac and cerebrovascular disease

▪ Early diagnosis is important to prevent irreversible pathology

▪ Diagnosis based on α-Gal A enzyme activity and/or genotyping

A systemic disease

Accumulation in manytypes of cells

▪ CNS

▪ Skin

▪ Heart

▪ Kidney

▪ Vascular endothelium

GI

Pain

Skin

Early symptoms

BrainHeartKidney

Late symptoms

Characteristic pictures in adults

Angiokeratomas

Cornea verticillata

≈15 year-delay from first symptoms to diagnosis

Mainly due to:▪ Nonspecific nature of early symptoms

▪ Heterogeneous phenotypes

▪ Lack of disease awareness among physicians

Fabry Outcomes Survey 2004

Specific signs to pediatric patients

▪ Acro-syndrome

▪ Acroparesthesia, pain attacks (extremities) ± fever

▪ Raynaud’s phenomenon

▪ Skin lesions (ear telangiectasias, small angiokeratomas)

▪ Hypo/anhidrosis, poor tolerance to cold and heat

▪ Eye abnormalities (conjuctival telangectasias, corneal whorls)

Laboratory diagnostic confirmation

DNA analysisFabry GLA gene mutation

FemalesFemales may have

normal to low-normal

enzyme activity

MalesMales typically have <1% of

normal enzyme activity in

plasma and leukocytes

α-GAL enzyme assayPlasma, leukocytes, cultured

skin fibroblasts, dried blood

Low activity

Fabry disease

diagnosis confirmed

DNA analysisFabry GLA gene mutation

Global Fabry nephropathy spectrum

GL-3 accumulation in renal cells

▪ End-stage renal disease in

3rd-5th decade of life▪ Premature death

Bu

rde

n o

f R

enal

Dis

eas

e

▪ Fabry nephropathy

▪ Proteinuria▪ Progressive GFR decline

▪ Hypertension

Albuminuria

Infant Child Adult Adolescent

Typical GL-3 inclusion bodies

Courtesy of Dr M Gubler, Necker Hospital Paris

Electron microscopy

Early progressive damage to podocytes

Decreased endothelial cell fenestrations

Glomerular basement membrane Loss of integrity of slit diaphragms

Capillary

Urinary space

Widened podocyte foot processes

Courtesy of Dr M Mauer, University of Minnesota

Electron microscopy

Progressive loss of GFR leading to RRT

Ortiz Nephrol Dial Transplant 2010

0

10

20

30

40

50

0 to < 25 25 to < 35 35 to < 45 45 to < 55 55 to < 65 >65

Age at First RRT (Years)

Per

cen

tage

of

Pat

ien

ts W

ith

RR

T

2

7

11

5

1 1

14

39

72

71

53

Males (n=186)

Females (n=27)

Fabry Registry patients (ERT naive) starting RRT:

▪14% males - 2% females

▪Median age: 38 years for both genders

▪Youngest patients starting RRT: age 15 in male – 17 in female

▪ESRD occurred most often in the 3rd to 5th decades of life

Management

▪ Optimal care involves disease-specific and supportive treatment

▪ Available therapies include:

▪ Enzyme replacement therapy (ERT) - agalsidase: Addresses the underlying pathophysiology by replacing deficient α-Gal A

▪ Adjunct therapies, e.g.

▪ Pain management (anti-psychotics, anti-epileptics, opiates, NSAIDs, etc.)

▪ ACEI/ARBs +++

▪ Renal replacement therapy

▪ Anti-depressants

▪ Hearing aids

▪ Cardiac pacing

Results of ERT on renal tissue

Germain J Am Soc Nephrol 2007

1-year follow-up of ERT in an 18 year-old male

Najafian PLoS ONE 2016

Baseline

12 mos on ERT

GL-3 exocytosisfrom podocytes

5-6 year follow-up of ERT in pediatric patients

Urine albumin/creatinine ratio mGFR

Plasma GL-3 Urine GL-3

Tøndel 2013

10 year follow-up of ERT

Germain J Med Genet 2015

Patients who initiated treatment at a younger age and with less kidney involvementbenefited the most from therapy. Patients who initiated treatment at older ages

and/or had advanced renal disease experienced disease progression.

Use of chaperone?

Germain N Engl J Med 2016

10. Peroxisomal disorders

▪ Zellweger syndromes Renal cysts

▪ Imerslund-Grasbeck syndrome LMW proteinuria

▪ Cobalamin deficiencies cblC, cblD, etc. HUS – Glomerulopathy

▪ MTHDH deficiency HUS

▪ Hypophosphatasia Nephrocalcinosis

11. IEM of vitamins and (non-protein) cofactors

12. IEM of trace elements and metals

▪ Wilson’s disease Fanconi – Proteinuria

▪ Menke’s disease Stones – CKD

▪ Molibdenum cofactor deficiency Xanthine stones

▪ Carbonic anhydrase II deficiency Mixed type of RTA

▪ Doss hepatic porphyria Urine turn red-purple

▪ Acute intermittent porphyria Urine turn red-purple – CKD

▪ Hereditary coproporphyria Hypertension

▪ Porphyria variegata Hypertension

13. IEM of porphyrin and heme

Conclusions

▪ A group of rare/heterogenous diseases

▪ Renal involvement is common in IEM, ranging from first-line presentation (e.g., cystinosis, APRT deficiency, etc.) to minor sign in a patient with major extrarenal involvement (e.g., metachromatic leucodystrophy, Lesch-Nyhan syndrome, etc.)

▪ IEM should be suspected in case of unexplained▪ Fanconi syndrome

▪ Nephrocalcinosis, nephrolithiasis (stone analysis ++)

▪ Proteinuria ±nephrotic syndrome (kidney biopsy ++)

▪ Atypical cystic disease

Mainly if associated with extrarenal abnormalities

▪ The managmeent relies on treating the primary defect

▪ The prognosis often depends on extrarenal involvement

Acknowkledgements

▪ Justine Bacchetta Lyon, France

▪ Francesco Emma Rome, Italy

▪ Georges Deschênes Paris, France

▪ Michel Tsimaratos Marseille, France

Thank you for your attention!